Abstract Non-alcoholic fatty liver disease/NASH are becoming the most common liver diseases in the US and worldwide. NASH is characterized by steatosis, inflammation leading to progressive fibrosis and cirrhosis. According to current concepts, disease progression from steatosis occurs after multiple ?hits? but the factors implicated in this are poorly understood. One of the most important factors in progression is oxidative stress. Chronic exposure to oxidative radicals leads to hepatocyte injury, cell death and either directly or indirectly to fibrosis. Therefore mitigating redox stress may result in broad effects and may help in halting or even reversing the disease. As there are currently no successful therapeutic strategies to treat NASH, novel approaches are urgently needed. NADPH oxidases (NOXs) are major sources oxidative radicals in the liver. NOX 1 and 4 are non phagocytic NOXs and are significantly induced in patients with NASH. Activation of these NOXs in stellate cells leads to their transdifferentiation to myofibroblasts and induction of collagen I. In hepatocytes NOX4 induction results in stress responses and cell death escalating inflammatory and fibrogenic responses. In recent animal studies inhibition of NOX1/4 by the novel inhibitor GKT137831 resulted in improved inflammation and fibrosis in animal models of NASH. In this phase 1/2A clinical study, we propose to evaluate the safety and efficacy of GKT137831 in adults with biopsy-proven NASH, with the overreaching goal of obtaining sufficient preliminary data to support further phase 2/3 studies. Our first specific aim is to evaluate the safety and tolerability of GKT137831 versus placebo in adults with NASH. Patient will be randomized to placebo or GKT137831 treatment and will be closely monitored for 48 weeks. Participants will be followed by the PI and co-Is in clinic visits, laboratory tests, and any adverse effects will be graded and recorded on an ongoing basis. Our second aim is to compare changes in liver stiffness based on magnetic resonance elastography (MRE) pre and post-treatment in adults with NASH, treated with GKT137831 versus placebo. The primary outcome measure will be a decrease in liver stiffness by >1.5 kPa at the end of treatment. Our secondary end points will include decrease in ALT, GGT and improvement of the homeostatic model assessment insulin resistance (HOMA-IR). The successful completion of the proposed studies will provide novel and clinically relevant information regarding a novel treatment approach in NASH, and will lead to data to support larger phase 2/3 trials.